'Poised on a Paradigm Shift': The REWIND and DECLARE Trials

Akshay B. Jain, MD: Welcome. My name is Dr Akshay Jain. I'm an endocrinologist in Surrey, British Columbia, and I have with me Dr Harpreet Bajaj, an endocrinologist in Toronto, Canada. He is also the vice chair of the Canadian guidelines for Diabetes Canada. Together, we're the columnists of The Sugar Beat on Medscape.

We're at the American Diabetes Association (ADA) 2019 Scientific Sessions here in sunny San Francisco, and we're very excited to share some of the latest research that has been presented—in particular, the REWIND trial[1] with dulaglutide and the DECLARE study[2] with dapagliflozin.

Harpreet, what do you think about the REWIND study?

Harpreet S. Bajaj, MD, MPH: I was an investigator in both the REWIND and DECLARE trials, so I know their ins and outs. Both of them are very important trials and were well conducted.

REWIND: Primary Prevention in Cardiovascular Disease

Bajaj: So let's talk about their clinical implications, starting with REWIND, which was a showstopper at ADA this year. I think it extends the cardiovascular efficacy benefit to a broader population than what we've seen in previous GLP-1 receptor agonist cardiovascular outcome trials like SUSTAIN-6, LEADER, or EXSCEL. This has a much broader, 70% primary prevention population and a large number of events—almost 600 events in that primary prevention population subgroup.

It does not show heterogeneity between secondary prevention versus primary prevention, suggesting that maybe there is a benefit even in primary prevention. So that is high-risk, not low-risk, primary prevention, for which we do not have previous cardiovascular disease outcomes.

Jain: Absolutely. And an important point to note is that this is one of the longest trials that we've had with a GLP-1 receptor agonist, at 5.5 years. That's ample time to see a large number of events, as you mentioned.

Also, the population was almost 46% women. We don't see that in cardiovascular outcomes trials, where females are usually underrepresented in the inclusion criteria.

Although many countries were involved, they did not have India and China, which collectively constitute about 30% of the total diabetes burden in the world. So it'll be interesting to see how these results would be applicable to all ethnicities.

'We Are Poised on a Paradigm Shift'

Bajaj: That's a good point. Now in the trial itself, another differentiator from other GLP-1 receptor agonist trials—or, for that matter, any other cardiovascular outcomes trial, whether it's with SGLT2 inhibitors or DPP-4 inhibitors—is that REWIND started at a very low A1c, with a 7.3 mean or 7.2 median A1c. And they still had a differential A1c effect with dulaglutide, better overall across 5.5 years by about 0.6% compared with the standard of care. I think this may have guideline implications for the future as well. What do you think?

Jain: I think that's a very important point. For the longest time, our approach to diabetes was that if you're not well controlled on a certain agent, then you add another agent, preferably one that has better cardiovascular protection or nephroprotection. But I think that we are poised on a paradigm shift with the way we're managing diabetes.

With the newer studies that we have, we could be looking at replacing; even if you're well controlled on certain agents, it would be a good idea to replace and get patients on a better agent, from the cardiovascular and nephroprotection point of view.

Bajaj: Very much so, and we should also state that any of these effects that we talk about, whether with REWIND or DECLARE, may actually be an underestimate of the cardiovascular benefit. We see in this trial that there was a 0.6% A1c difference, but these trials are mandated to keep the A1c difference tight by adding additional therapies to the placebo group that lower that differential.

I think if that differential were to be allowed like it is, for example, in LDL-lowering trials with statins, then we'd see even more robust cardiovascular or chronic kidney disease benefits.

Jain: Potentially. I think this also speaks to the pleiotropic benefit of these medications—apart from glucose lowering, what else they can potentially achieve. And the day is not far when cardiologists and nephrologists may be using these agents much more than endocrinologists do.

DECLARE Extends Renal Benefit to Lower-Risk Population

Bajaj: Yes. Speaking of nephrologists, the DECLARE trial extends the robust data that we've seen from the CREDENCE trial. The new data that were presented here at ADA suggest that there may be benefit even in the lower-risk chronic kidney disease population. CREDENCE, of course, had a high-risk chronic kidney disease population. So this suggests that dapagliflozin may extend renal protection to a lower-risk population as well.

Jain: Yes. I think the unifying thread for the CREDENCE and DECLARE renal outcomes was that the population with macroalbuminuria tended to have maximum benefit on this class of agents. So again, speaking from the clinical implications point of view, I think we're not too far from the day when guidelines may suggest that after using ACE inhibitors or ARBs for nephroprotection, the next go-to agent should be an SGLT2 inhibitor.

Safety Is 'Reassuring,' but Costs Are High

Bajaj: And great safety as well. If you're talking about acute renal injury from DECLARE, great results in favor of dapagliflozin versus placebo. REWIND had over 50,000 person-years of data and DECLARE had over 30,000 person-years of data, just from one randomized trial each. It gives us a lot of safety information, which we would not have had for these agents otherwise. And nothing new came out as a potential adverse event, which is very reassuring.

Jain: I think it reassures the clinician that we can continue to use these agents without expecting anything out of the ordinary in terms of side effects.

Bajaj: Yes. And we should keep in mind that both of these classes of agents—GLP-1 receptor agonists and SGLT2 inhibitors—are diabetes agents. We are using them for A1c lowering, weight lowering, and other effects, but cardiovascular or kidney disease benefits may be seen as a bonus effect.

The cost implications are key as well. We know that these classes of drugs are quite expensive. Cost is almost like a fifth vital sign, if you will, and it needs to be considered in the individualization of therapy for each patient with diabetes.

Jain: I hope future studies will address the long-term cost benefit in terms of the healthcare resources that are being utilized, to see if we are preventing major adverse cardiovascular events (which would probably mitigate the individual cost of these agents) and how much we can benefit from the healthcare resource spending point of view. We need those cost-benefit analysis studies to be done.

Bajaj: That's great, Akshay. It was a pleasure. I hope that our Sugar Beat column is useful to you. We look forward to your feedback and comments on our discussion about REWIND and DECLARE, or any past or future Sugar Beat columns. Thank you.

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