Cardiovascular Outcomes Trials Give 'Comforting' Results

Anne L. Peters, MD


December 13, 2018

You may be slightly bored hearing about cardiovascular outcomes trials by now, but I still find them fascinating and think they're worth discussing.

DPP-4 Inhibitors and Congestive Heart Failure

In terms of the dipeptidyl peptidase-4 (DPP-4) cardiovascular outcomes trials, none of them have shown a cardiovascular benefit, and they seemed pretty neutral to me. However, when we received the results of the SAVOR-TIMI trial, there was an increased risk for congestive heart failure (CHF) in patients who were treated with saxagliptin.[1]

This was a concern, and there is now a warning from the US Food and Drug Administration (FDA) on the label of the DPP-4 inhibitors saying that saxagliptin can increase the risk for CHF.

I have not really seen this in my own practice, and I've always felt that the DPP-4 inhibitors were pretty safe for patients who were more frail or perhaps at more risk for CHF. DPP-4 inhibitors don't cause hypoglycemia and they're easy to use.

There was absolutely no difference between linagliptin and placebo in terms of heart failure hospitalizations.

The CARMELINA trial, which included patients with type 2 diabetes who were treated with linagliptin, showed that there was not only no particular benefit but also no risk for an increased rate of CHF.[2]

The patients in CARMELINA had type 2 diabetes and concomitant atherosclerotic cardiovascular disease and/or kidney disease, so these are actually patients at high risk of developing CHF. Nearly 7000 patients were included in this trial.

When these data were analyzed, there was absolutely no difference between linagliptin and placebo in terms of heart failure hospitalizations. This was reported in patients who hadn't had CHF and in those who had had episodes of CHF.

Looking at the CARMELINA data, I was comforted and felt confident that, at least with linagliptin, there was no increased risk for CHF—at least not in this high-risk population that they studied.

This has been true with the other DPP-4 inhibitors, including sitagliptin. Only saxagliptin showed an increased risk for CHF, so I was comforted by the results of the CARMELINA trial in terms of not causing harm when giving patients linagliptin.

SGLT2 Inhibitors in Patients Without Cardiovascular Disease

Moving on to sodium-glucose cotransporter-2 (SGLT2) inhibitors, we have the DECLARE-TIMI trial.[3] This is a trial in patients with type 2 diabetes, but it is different from other trials because there were many patients who had not had a cardiovascular event. If you look at the EMPA-REG trial, almost all of those patients had preexisting cardiovascular disease.[4]

In DECLARE-TIMI, they enrolled more than 17,000 patients, both primary and secondary prevention, including 10,000 who did not have known cardiovascular disease. Patients were randomized to placebo or to dapagliflozin. The data from this study are slightly complicated, but again, this isn't the same group of patients that was studied in the other cardiovascular outcomes trials for SGLT2 inhibitors.

The DECLARE-TIMI trial asks the question, 'How beneficial are these agents in patients without known cardiovascular disease?'

In this population, [participants treated with dapagliflozin] did not have significantly lower major adverse cardiac events (MACE), but they did have a significantly lower risk for cardiovascular disease or hospitalization for heart failure compared with placebo, and there were improvements in terms of renal outcomes.

This trial showed me that even though MACE didn't reach statistical significance, which changes how you analyze all the rest of the data, the results looked like that of a fairly typical SGLT2 inhibitor in that dapagliflozin reduced rates of CHF. [Dapagliflozin treatment also reduced cardiovascular death and demonstrated] potential benefits in terms of renal outcomes.

To compare dapagliflozin with the other two SGLT2 inhibitors, both empagliflozin and canagliflozin reduced MACE in their respective trials. Empagliflozin also reduced cardiovascular death.

Again, remember that these populations had more cardiovascular disease than participants in the DECLARE-TIMI trial. EMPA-REG almost only included patients who were secondary prevention, and CANVAS included a mix,[5] but 60% of patients were secondary prevention. The FDA has now included cardiovascular benefit in the labels for both empagliflozin and canagliflozin.

The DECLARE-TIMI trial asks the question, "How beneficial are these agents in patients without known cardiovascular disease?" We certainly believe that SGLT2 inhibitors are beneficial both in patients who have known cardiovascular disease and in patients who are at risk of developing CHF. Again, SGLT2 inhibitors may be beneficial in all of these cases in patients with renal dysfunction.

A Look Ahead to REWIND

Moving to glucagon-like peptide-1 (GLP-1) receptor agonists, we received a report that dulaglutide, a once-weekly GLP-1 receptor agonist, helps reduce cardiovascular events.[6] This trial is called REWIND and we don't have all of the data yet—we're not getting that until June 2019.[7] The headline data were released, which said that dulaglutide significantly reduced the rates of MACE in this trial.

This is very important to me because there has been a question in my mind about whether the cardiovascular benefit of GLP-1 receptor agonists is a class effect or whether it is specific to liraglutide, where we saw a nice benefit in terms of cardiovascular outcomes.

The suggestion of benefit with dulaglutide in this press release is very comforting to me because I think the GLP-1 receptor agonists are probably beneficial in terms of reducing cardiovascular events, and it's nice to get confirmation of that fact.


Let's sum up the data that have come out recently. First, linagliptin did not increase the risk for CHF in high-risk patients or in patients who had preexisting cardiovascular disease and CHF, so that's comforting. DPP-4 inhibitors may not be so concerning in terms of CHF except for saxagliptin and, potentially, alogliptin.

Second, the SGLT2 inhibitor class seems to be beneficial in a variety of ways—cardiovascular risk reduction, cardiovascular death, CHF hospitalization—with benefit in terms of renal function. There were differences in the patient populations in the trials, but there seemed to be benefits throughout.

Finally, we now have data suggesting that the GLP-1 receptor agonist benefit in terms of cardiovascular risk reduction is going to be a class effect. To determine this, we need the full details of the REWIND trial, which will be coming out in June.


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