Earlier this month I shared my excitement in attending the 2016 Global CardioVascular Clinical Trialists (CVCT) Forum. In collaboration with my colleague Dr Rick Turner, I’d like to provide this report on two aspects of the meeting that were pertinent to patients with chronic kidney disease (CKD).
At this year’s event, I served as a panelist for the session entitled “Cardiovascular Drug Trials — and the Lack Thereof — in Late Stage CKD.” The discussions were wide-ranging, and I was able to share the unique contract research organization (CRO) perspective with our participants.
One of the key messages of this panel was that cardiovascular disease in CKD patients has different pathology from that in the general population, which is partly why drugs with proven efficacy in non-CKD patients don’t always benefit them. Similarly, CKD patients face different safety issues, and therefore our trials seem to terminate earlier and more often than other therapeutic areas.
Because we cannot simply extrapolate data from other trial populations to serve our CKD patients, we need to do a better job of tailoring our protocols to specific CKD populations with cardiovascular endpoints that are appropriate to their pathology. For example, we may need to establish distinct CKD-related definitions for heart failure and myocardial infarction — some authorities believe sudden cardiac death and hemorrhagic stroke are more important outcomes in CKD patients than myocardial infarction.
We also need to redefine renal endpoints to align with realistic event rates to ensure our protocols are feasible and can demonstrate an effect in shorter timeframes. For CKD patients, experiencing a cardiovascular outcome is more prevalent than reaching end-stage kidney disease, and therefore this should be considered more often in our composite endpoints.
These themes mirror discussions held at other nephrology meetings I attended this year, including the Global KDIGO meeting: Challenges in Nephrology Trials, and the Kidney Health Initiative. However the unique benefit of the CVCT Forum was the opportunity to directly engage with our cardiovascular and endocrine colleagues.
Big news from FDA
It was also of great interest to attendees at the CVCT Forum that the United States Food and Drug Administration (FDA) made a very high-profile announcement regarding empagliflozin, a sodium-glucose co-transporter 2 (SGLT-2) inhibitor that was approved by FDA in August 2014 as an addition to diet and exercise to improve glycemic control in adults with type 2 diabetes (T2D). During the forum session entitled “Diabetes Outcome Trials: Transitioning from Safety to Efficacy Trials,” speakers and panelists, including Rick Turner, discussed a series of cardiovascular safety outcome studies that had been conducted following FDA’s 2008 requirement to provide compelling evidence exonerating new antidiabetic drugs for T2D from unacceptable cardiovascular risk.
As examples, the SAVOR-TIMI 53 (saxagliptin), EXAMINE (alogliptin), and TECOS (sitagliptin) outcome studies demonstrated that these antidiabetic drugs did not increase cardiovascular risk to an unacceptable degree. However, more recent outcome studies have gone one step further by providing evidence of cardiovascular benefit: these include EMPA-REG OUTCOME (empagliflozin), LEADER (liraglutide), and SUSTAIN-6 (semaglutide).
The Forum session included discussions addressing whether regulatory agencies would find evidence from these studies compelling enough to issue new indications for cardiovascular benefit. In particular, attention focused on empagliflozin and the EMPA-REG OUTCOME study results since they had been considered by FDA’s Endocrinologic and Metabolic Drugs Advisory Committee on June 28th 2016. The Committee voted 12 (yes) to 11 (no) that the EMPA-REG OUTCOME study results provided substantial evidence to establish that empagliflozin reduces cardiovascular mortality in the population studied in that trial. The next day, FDA announced that empagliflozin had been given a new indication to reduce the risk of cardiovascular death in adult patients with T2D and established cardiovascular disease. This new indication, and potentially similar indications for other antidiabetic drugs, may have far-reaching implications in the treatment of individuals with T2D and cardiovascular disease.
Of particular importance to the CKD community, a subsequent report from the EMPA-REG OUTCOME investigators found that empagliflozin was associated with slower progression of kidney disease and lower rates of clinically relevant renal events than placebos when added to standard care in individuals with T2D at high cardiovascular risk
The potentially far-reaching consequences of the FDA’s announcement will be of considerable interest to many clinical scientists and physicians in the areas of endocrinology, cardiology, and nephrology. I look forward to providing additional updates in this area in the coming months.