Editor's Note: Dr. Deepak Bhatt was the International Co-Principal Investigator of the SAVOR-TIMI 53 Trial. He presented the main results at ESC Congress 2013.

At the European Society of Cardiology 2013 meeting in Amsterdam, two late-breaking clinical trials were presented and simultaneously published in the New England Journal of Medicine. These two studies were the first in a series of large cardiovascular outcome trials of novel drugs used to treat diabetes mellitus.

The SAVOR-TIMI 53 trial (Slide 1) was the larger of the two studies. A total of 16,492 patients with type 2 diabetes mellitus and either established cardiovascular disease or multiple cardiovascular risk factors were randomized to receive either the dipeptidyl peptidase-4 (DPP-4) inhibitor saxagliptin or placebo. The overall hazard ratio for cardiovascular death, myocardial infarction, or ischemic stroke was 1.00, with a 95% confidence interval of 0.89-1.12; the p value for non-inferiority was <0.001 and for superiority was 0.99. Similarly, the hazard ratio for a more comprehensive secondary cardiovascular endpoint was 1.02. Unexpectedly, there was an excess in one component of the secondary endpoint, hospitalization for heart failure (Slide 2). While statistically significant, in absolute terms, the excess in hospitalization for heart failure was only 0.7% over two years, and there did not appear to be any significant excess in mortality associated with this finding. Analyses are ongoing to understand better this observation.

The EXAMINE trial (Slide 3) randomized 5,380 patients with type 2 diabetes mellitus and a recent acute coronary syndrome to the DPP-4 inhibitor alogliptin or to placebo. The overall hazard ratio for the primary endpoint of cardiovascular death, myocardial infarction, or stroke for alogliptin versus placebo was 0.96, with an upper boundary of the one-sided repeated confidence interval of 1.16; the p value for non-inferiority was <0.001 and the p value for superiority was 0.32.

Both trials were initially designed in response to the United States Food and Drug Administration (FDA) requirement that new diabetes drugs establish cardiovascular safety in order to remain on the market. Both trials met the criteria laid out by the FDA, which was that the upper bound of the 95% confidence interval for the hazard ratio for ischemic events be less than 1.3.

The results of both trials were largely concordant, especially with respect to the primary cardiovascular safety endpoint each trial was designed and powered to test. Therefore, these trials provide reasonable confidence that DPP-4 inhibitors as a class are safe, both from a cardiovascular perspective, and also in general. Nevertheless, it will be important for the ongoing trials of other DPP-4 inhibitors, as well as novel diabetes drugs such as the SGLT-2 inhibitors, to continue their planned mega-trials. It is only with trials of such magnitude that rare side effects may be detected and the full cardiovascular and general safety of diabetes drugs can be established.

There were some differences between the trial results, though. The increase in hospitalization for heart failure has been published for SAVOR-TIMI 53. Heart failure was adjudicated in EXAMINE as well, but those results have only recently been presented at the EASD 2013 in Barcelona. The reported hazard ratio for hospitalization for heart failure was 1.19, though the p value was not significant, possibly due to the fact that EXAMINE was about one third the size of SAVOR-TIMI 53. Potentially, the increase in hospitalization for heart failure is a class effect of DPP-4 inhibitors. It remains possible that the increase in heart failure is a consequence of tighter glycemic control, as heart failure has also been associated with the use of the thiazolidinediones rosiglitazone and pioglitazone. Ongoing and future trials of diabetes drugs should pre-specify and adjudicate heart failure as an endpoint to clarify the above observations.

There was also an increase in hypoglycemic events noted in SAVOR-TIMI 53, but not in EXAMINE. However, there was no increase in hospitalization for hypoglycemic events in SAVOR-TIMI 53. Likely, the differences in trial results were due to the different trial populations and the differing definitions of hypoglycemia used, with a much more sensitive definition in SAVOR-TIMI 53.

Pancreatitis had been a concern with DPP-4 inhibitors based on observational data. Neither randomized, blinded trial found a significant difference in pancreatitis. Additionally, neither trial found an excess in pancreatic cancer, which had also been raised by some as a concern based on preclinical data. Once again, the value of randomized clinical trials over observational or animal data is demonstrated.

The lack of any hint of benefit on cardiovascular outcomes in either trial is also noteworthy. Does that mean that reduction in hemoglobin A1c does not reduce macrovascular events? Neither trial was optimally designed to test that hypothesis. It would be necessary to conduct a much larger, longer term study. Furthermore, there would need to be a greater contrast between treatment arms than is likely to be attained in trials in which add-on diabetes therapy is allowed, which will probably be greater in the control arm than in the active arm. In SAVOR-TIMI 53, the hemoglobin A1c at two years was 7.5% in the saxagliptin arm and 7.8% in the control arm, p<0.001. In EXAMINE, there was a similar 0.36% reduction in the hemoglobin A1c for alogliptin versus control, p<0.001. In the absence of some pleotropic effect, those differences in hemoglobin A1c would not be expected to reduce macrovascular events over the durations of follow up of these two trials.

What about microvascular events? Again, neither trial was designed to capture these types of events, and a much longer period of observation would have been necessary. Older data support the strong association between reduction in hemoglobin A1c and lower risk of microvascular events. However, a critic might state that the newer diabetes drugs, such as DPP-4 inhibitors, have not directly been demonstrated to lower microvascular events, so while logical to expect they do, it is still an assumption that hemoglobin A1c reduction by any means provides equivalent microvascular benefit.

Thus, overall these two trials provide reassurance that DPP-4 inhibitors are a reasonably safe therapy to use for type 2 diabetes mellitus. They clearly do not raise myocardial infarction risk, which has been a concern with other classes of diabetes drugs. Cancer rates, liver damage, and fracture risk — which have been associated with other diabetes drugs — were not noted to be significantly elevated in these two trials of DPP-4 inhibitors. The data (and cost) do not support their use as first-line agents, but in patients who need add-on therapy, this class of medications now has a large evidence base upon which physicians can make informed decisions for their patients about which agents to use for attaining glycemic control while weighing the cardiovascular and general safety of diabetes drugs. Both drugs seem to be useful in lowering hemoglobin A1c to target, though neither trial tested nor supports aggressive lowering of hemoglobin A1c in older patients with longstanding diabetes and established cardiovascular disease, consistent with current recommendations for more liberal targets (e.g., <8%) in this population. Furthermore, other approaches will be necessary to reduce actual cardiovascular risk in diabetic patients.

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References

1. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus. N Engl J Med 2013. [Epub ahead of print].
2. White WB, Cannon CP, Heller SR, et al. Alogliptin after Acute Coronary Syndrome in Patients with Type 2 Diabetes. N Engl J Med 2013. [Epub ahead of print].

Keywords: Diabetes Mellitus, Prescription Drugs

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