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The #CREDENCE Trial was discussed @NephJC last night. We were fortunate to have the lead author of the paper @VladoPerkovic join in. He took questions from the participants. Here is the summary of his responses 👇🏽
Q1: Why was the 100 mg dose of Canagliflozin used in #CREDENCE and not the 300 mg dose?
VP: We were anxious about the toxicity as seen in some previous trials, & we wanted to minimize that risk
Q2: Why did centers from Germany have a lower HbA1C cut off for inclusion in the study compared to the centers from other parts of the world - 10.5% vs. 12%?
VP: That was a regulatory request from Germany 🇩🇪
Q3: Why was only 5% of the CREDENCE trial population black?
VP: Fair point. We worked really hard to recruit them but it was hard. Please note that the trial was global, and more than 15% of the participants from the US were African American
Q4: Are there any protocols in place to stop the drug - should we follow ‘Sick Day’ rules?
VP: Good point. Pts. in the trial were advised to consider stopping diuretics, Anti-HTN meds if required & we tried to maintain RAS blockade & the study drug
Q5: Hyperkalemia was not seen in CREDENCE, but has been seen in some previous SGLT2 Inh. trials?
VP: K variation in previous trials likely due to chance, would expect K to be lower given the mechanism of the drug, and that was the case in CREDENCE
Q6: Does the duration of DM impact the outcomes seen with the use of Canagliflozin?
VP: I don’t think so
Q7: Is the Reno-protection seen with Canagliflozin a dose-dependent response?
VP: I don’t think so. No evidence of dose response effect has been seen in the previous trials #CANVAS or #EMPA-REG Outcomes
Q8: Pts. in the eGFR range of 60-90 mls/min did not get as much benefit as the pts. w/ lower eGFR?
VP: I would recommend not over- interpreting individual sub-group outcomes. Also, previous trials strongly suggest renal benefit at eGFR >60 mls/min
Q9: Did anyone expect a 30% risk reduction in the renal outcomes in pts. already on maximum RAS blockade?
VP: I did not - at least not in 2013
Q10: The Reno-protective effect seems to continue over time?
VP: It appears to be strong and ongoing
Q11: The DSMC recommended early stoppage of the trial due to the overwhelming benefit seen with the Study drug. Was there a debate over this?
VP: No debate, it was a clear decision #NephJC
Q12: It was fascinating to see differing referral patterns for CKD pts. among different countries?
VP: Huge variability,some DM-CKD pts. were referred as soon as they developed albuminuria & some not till it was time to start dialysis -wide spectrum
Q13: Anyone looking at using these drugs in the transplant patients?
VP: Imp. population to study. Will be imp. to learn the risk of infection w/ use of these drugs in the transplant pts. No data is currently available to the best of my knowledge
Q14: The policy implications of #CREDENCE r enormous & have a chance of shaping future delivery of care to diabetic CKD patients
VP: This is going to be our next challenge. We don’t even give RAS blockade to all who might benefit from them..
Q15: Would it be correct to say that NNT is about 22 for primary composite outcomes?
VP: Yes - Treat 22 Patients for 2.5 years to prevent 1 primary outcome, or among 1000 patients treated for 2.5 years, 47 cases were prevented
Q16: Amputation risk was not higher in CREDENCE but a protocol amendment was made in May 2016 to examine pt’s feet at each visit & hold the drug - any comments?
VP: Holding SGLT2 Inhibitors in pts. w/ foot lesions is sensible
Q17: How soon would you recommend following the patients after initiating SGLT2 Inhibitors?
VP: In CREDENCE, we brought the patients back in 3 weeks to check BP, volume status and adjust other medications if required
Q18: Genital mycotic infections can be Rx w/ a single dose of PO anti-fungal drug or topical anti-fungal cream - not a life threatening side effect?
VP: Yes, such infections rarely lead to problems, most Rx w/ topical cream
w/o stopping SGLT2 Inh.
Q19- Genital mycotic infection risk?
VP: Risk is small but need to be careful in uncircumcised men as some cases of phimosis have been reported
Q20: The Study wasn’t powered for adverse events?
VP: True - The # of amputations in CREDENCE were 70% the # seen in CANVAS, but the placebo gp. had 4X the risk in CREDENCE. Note the p-value for heterogeneity for amputation b/w the 2 Trials was 0.02
Q21: What was the absolute risk reduction in the study - this makes more sense to the Nephrologists?
VP: About 2% for the primary outcome
Q22: Interested to know: If all patients were to receive SGLT2 Inhibitors alone and the RAS blockade was added on, then would the addition of RAS blockade be synergetic?
VP: Interesting question for the future...
@VladoPerkovic @NephJC @hswapnil @kidney_boy - In case I have made any errors in representing the questions or the answers in this thread then please feel free to make amendments. Thanks!
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