COMMENTARY

How Do the Renal Data From CREDENCE and CARMELINA Compare?

Meg J. Jardine, MBBS, PhD; Christoph Wanner, MD

Disclosures

June 25, 2019

This transcript has been edited for clarity.

Christoph Wanner, MD: Hello. I'm Christoph Wanner from the University of Würzburg in Germany, and I'm joined today by Meg Jardine from the George Institute for Global Health in Australia. We are going to discuss the renal outcomes from the CREDENCE and CARMELINA trials today. Meg, can you give us the basic results of the CREDENCE study?

Meg J. Jardine, MBBS, PhD: Essentially, what we found in CREDENCE[1] was a 30%-34% reduction for the various outcomes we looked at. The main outcome was a doubling serum creatinine, end-stage kidney disease, or renal or cardiovascular death. We looked at a range of other outcomes and got pretty concordant results. This was very exciting news for patients.

Wanner: You investigated a sodium-glucose cotransporter 2 (SGLT2) inhibitor?

Jardine: We did. We randomized patients to 100 mg daily of canagliflozin or matching placebo, and they stayed on that treatment throughout the study unless they started dialysis or received a transplant.

Wanner: In CARMELINA,[2] a cardiovascular safety and efficacy trial, we randomized patients to linagliptin 5 mg [or placebo] daily over a median study duration of 2 years. These study interventions are different in that canagliflozin is an SGLT2 inhibitor and linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor. How do the participants compare between the two?

Jardine: Because we wanted to look at renal outcomes, we recruited a population at high risk for renal events. We had patients with an estimated glomerular filtration rate (eGFR) between 30 and 90 mL/min per 1.73 m2, but we specifically targeted 60% of the total population under 60 mL/min per 1.73 m2. We only recruited people with high levels of albuminuria—more than 300 mg/g. So they were a high-risk population.

Wanner: What was the mean eGFR?

Jardine: Our mean eGFR finding was 56 mL/min per 1.73 m2. We did get 60% with an eGFR < 60 mL/min per 1.73 m2 and we had a median urine albumin-to-creatinine ratio (UACR) of around 928 mg/g.

Wanner: It was exactly the same eGFR in CARMELINA—56 mL/min per 1.73 m2. But the inclusion criteria were different. We sampled patients with type 2 diabetes all over the world with an eGFR < 60 mL/min per 1.73 m2 and patients > 60 mL/min per 1.73 m2 who had albuminuria. At the end we came to the same eGFR level. Overall, the UACR for participants in the trial was only 164 mg/g, so there was less albuminuria.

Jardine: Particularly in that lower eGFR group, right?

Wanner: The next difference was that CARMELINA is a cardiovascular outcome trial and the kidney outcomes are secondary outcomes, which are more or less exploratory and not so robust as in your trial.

Jardine: Different goals. What were the cardiovascular results?

Wanner: As in all DPP-4 inhibitor trials, they were neutral. Both groups were similar, but if the CARMELINA trial is unique in accumulating high-risk kidney patients, and if the intervention is safe in this vulnerable group of patients, then that is a good message for patients and doctors when they want to use linagliptin in this high-risk group.

Jardine: It is so important to test safety in patients with impaired kidney function, and they are often left out of trials. So congratulations on completing CARMELINA.

Wanner: Linagliptin had no impact on eGFR; I hoped we'd have seen something.

Jardine: It's interesting that you didn't see an impact on eGFR. Do you think 2 years was long enough for this type of agent?

Wanner: If you go back to the mechanism of action of these drugs, the hemodynamic effects of SGLT2 inhibitors occur more rapidly than maybe the antifibrotic effects of DPP-4 inhibitors, so it could be that a 2-year duration was too short.

Jardine: You have to tailor the duration to the putative mechanism of action.

Wanner: Right. In the future, we would like to look more at slopes of eGFR, and we should see at least a tiny difference after 2 years. As far as the data I have seen, it does not appear that there is an effect on slopes of eGFR, and it could be that DPP-4 inhibitors just have no major impact on function in the short run.

Jardine: That is a good point. The ADVANCE trial[3] was a glucose-lowering trial, and there was an impact on renal outcomes, but that was apparent at 10 years of follow-up. So maybe sometimes you do have to wait longer to also see the impact of glucose control.

Wanner: I absolutely agree. As expected, linagliptin had an effect on lowering of albuminuria. This is becoming more important in nephrology, and I think we will take this success in lowering albuminuria forward by considering combination therapy in the future. What do you think?

Jardine: I think that would be a terrific direction because, as you point out, there are two complementary parts of our management strategies, and it would be good to test the two together and see how they work in complementary fashions.

Wanner: I have already outlined the safety of CARMELINA, which I think for doctors is a very good message. How was the safety in CREDENCE?

Jardine: It was reassuring, which was good to see. We saw fewer adverse events in patients on canagliflozin than on placebo. We saw no effect on amputation or on fracture. We did see some adverse events. Mycotic genital infections were elevated as in other SGLT2 inhibitor trials, but there was no impact on urinary tract infections, which was interesting and good to see. So, overall, there was a reassuring message.

Wanner: One class of drugs is unlikely to address all of the renal risk, but 3 years ago we had nothing. And now we have these beautiful trials dominated by the SGLT2 inhibitors and these prominent effects. Then we see glucagonlike peptide 1 (GLP-1) receptor agonists coming and DPP-4 inhibitors. I think the future is good for a kidney patient.

Jardine: That is quite true. Suddenly we are seeing a proliferation of trials looking at different mechanisms that might have an impact on diabetic kidney disease. It's so important, isn't it? Dialysis units are full of patients who have got there through diabetes, so we really need to keep exploring all of these mechanisms.

Wanner: Kidney doctors are excited because we have new instruments in our hands.

Jardine: Yes, it's a really hopeful point. As you said, the past 10-20 years have been a little concerning, but now, suddenly there is a wave of activity, and I think we are making an impact on the disease, which is great.

Wanner: Thanks to the audience for attending our short discussion. We hope it was helpful.

Jardine: Thank you, Christoph.

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