Peeking Inside Schrödinger’s Box

Nephrology Times welcomes Joel Topf, MD as a contributor. Dr. Topf is an assistant clinical professor of medicine at Oakland University William Beaumont School of Medicine, creator and host of the Freely Filtered and Channel Your Enthusiasm podcasts, creator of the Precious Bodily Fluids blog, and co-creator of NephMadness and NephJC.

Vlado Perkovic has not presented the results of the FLOW trial, but the surprise is gone. We know what he is going to say. On March 5, Novo Nordisk released the top-line results from this pivotal kidney outcomes trial: Use of semaglutide in patients with diabetic kidney disease reduced the primary outcome—a composite of kidney failure, 50% decline in estimated glomerular filtration rate (eGFR), and cardiovascular (CV) or kidney death—by an impressive 24% (Figure 1).

Figure 1. Design and Baseline Characteristics of the FLOW Trial of Semaglutide in Patients With Type 2 Diabetes and Chronic Kidney Disease

If this sounds like déjà vu, that may be because Novo Nordisk previously implied that FLOW was positive on October 10, 2023, when the trial was stopped early for efficacy (Figure 2).

Figure 2. Vlado Perkovic Tweets That They Are Stopping FLOW Early for Efficacy

We will have to wait for the presentation and publication of the manuscript to fully understand the details and cost-benefit implications of semaglutide in chronic kidney disease (CKD), but this result was not unexpected. The FLOW trial was undertaken after earlier cardiovascular outcome trials (CVOT) revealed clues to improved kidney outcomes.

We have seen this play out before. In 2015, EMPA-REG was published. The trial was designed to fulfill the US Food and Drug Administration (FDA) requirement that diabetes medication prove cardiovascular safety prior to approval. EMPA-REG not only showed that empagliflozin was safe, but it also showed a stunning, and largely unexpected, reduction in CV mortality, heart failure admissions, and total mortality (Figure 3). The investigators also tracked renal outcomes, and those were equally stunning (Figure 4). However, the patients enrolled in EMPA-REG had little CKD at the start of the trial. This fact, paired with the relatively short duration of follow-up, meant there were few renal outcomes and the benefits were largely extrapolated from reductions in proteinuria.

Figure 3. EMPA-REG Outcome Visual Abstract

Figure 4. EMPA-REG Kidney Visual Abstract

While empagliflozin was the first out with a CVOT, canagliflozin was the first to complete a kidney-focused flozin trial, CREDENCE, which convincingly answered any doubts from the earlier trials. CREDENCE enrolled patients with established diabetic kidney disease—patients who we see filling our CKD clinics and, unfortunately, filling our dialysis units (Figures 5 and 6).

Figure 5. Visual Abstract From CREDENCE

Figure 6. Incidence of ESRD by Etiology; Data From the USRDS Atlas

In CREDENCE, taking canagliflozin prevented death, dialysis, and progression of CKD. After CREDENCE came DAPA-CKD, showing that dapagliflozin did not just save diabetic kidneys but also saved kidneys in patients with any proteinuric kidney disease. Finally, in 2022, EMPA-KIDNEY showed that empagliflozin provided benefit in patients with CKD without regard for diabetes or proteinuria.

Right now, nephrology is poised as we were before the release of CREDENCE. We have seen the data that glucagon-like peptide receptor agonists, GLP-1s, reduce CV events and mortality. SUSTAIN-6, which showed cardiovascular safety for semaglutide, also had a flozin-like 26% reduction in CV death, heart attack, or stroke (Figure 7).

Figure 7. Semaglutide CVOT, SUSTAIN-6 Visual Abstract as a GIF

In fact, Novo Nordisk used data like these to gain a new indication for semaglutide just last week:

Today, the [FDA] approved a new indication for use for Wegovy (semaglutide) injection to reduce the risk of cardiovascular death, heart attack, and stroke in adults with cardiovascular disease and either obesity or overweight. Wegovy should be used in addition to a reduced-calorie diet and increased physical activity. Cardiovascular disease is a group of diseases of the heart and blood vessels.
—FDA News Release

Additionally, if you look at all the GLP-1s, this appears to be a class effect. Though none of the studies have looked at a population at high risk of kidney outcomes, there is a consistent drumbeat of improved renal surrogate outcomes (Figure 8).

Figure 8. Renal Outcomes From the CVOT for Various GLP-1s

We are going to get the FLOW results in the next few months. A little birdie whispered that we can expect Vlado Perkovic to take the stage at the 61st European Renal Association Congress in Stockholm, Sweden, in late May.

But the exact time doesn’t matter. We are going to see the results soon. They will be positive. And a year from now, the FDA will announce the approval of yet another medication that slows the progression of CKD. While on the surface that may sound like just another angiotensin-converting enzyme inhibitor or flozin, this will be a drug that patients will be knocking down your door to get.

How many patients with CKD do you have who want to lose a few pounds and would benefit from better glycemic and/or blood pressure control? Yeah, all of them.

I am already seeing amazing effects from these medications. I have a steady stream of patients on semaglutide who are coming in 10 to 20 pounds lighter, with blood pressure so much better that I am stopping (some of) their blood pressure medications. They are also reducing or stopping their insulin.

But the GLP-1s are not the benign, nearly invisible, drugs that flozins are. GLP-1s come with a high rate of side effects, which we will need to become skilled at avoiding and treating. Just as nephrologists are adept at detecting and managing the hyperkalemia of renin-angiotensin-system (RAS) inhibitors, we will need to master the art of treating the gastrointestinal disorders that are found in over half the recipients of GLP-1s (Figure 9).

Figure 9. Adverse Events From Semaglutide

GLP-1s are on the verge of remaking CKD. This remarkable drug seems to correct the metabolic derangements that are driving our CKD epidemic. If we can actually get this drug into our patients, we are going to see an even more profound reduction in the epidemiology of CKD that was kick-started by RAS inhibitors 2 decades ago and amplified by flozination in the last few years.