A long awaited analysis of the renal outcomes from the EMPA-REG study was published in the New England Journal of Medicine on June 14th . As originally reported on UKidney, compared to patients taking placebo, the use of empagliflozin was associated with significant improvements in important renal end-points, namely doubling of serum creatinine and end-stage renal disease (ESRD). While these results are indeed very promising, some perspective is warranted when considering the potential nephroprotective properties of this drug, and of the SGLT2 inhibitor class in general.
UKidney Nephrology News and Insights
The SPRINT Study was received with great fanfare when it was published on November 26th in the New England Journal of Medicine. The primary results, summarized in the publication’s abstract are these:
"Among patients at high risk for cardiovascular events but without diabetes, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, resulted in lower rates of fatal and nonfatal major cardiovascular events and death from any cause, although significantly higher rates of some adverse events were observed in the intensive-treatment group."
The essential word in that abstract’s conclusion - and which prevents the application of these results - is ‘targeting’. The conclusion accepted by many is that aggressive blood pressure reduction, that is the achieved blood pressure, drove the observed results. However, it may well be that the act of targeting a low blood pressure, and using cardioprotective drugs to do so, explained the results rather than the reduction of blood pressure itself. And unravelling this nuance is the key to understanding whether SPRINT’s main message is applicable to the general population. I would argue that in its current form SPRINT suffers from a major methodological short-coming that leaves us in a quagmire.
As we continue to process data from the EMPA-REG renal outcomes presentation - which most importantly showed a 46% reduction in the composite of creatinine doubling, end-stage renal disease or renal death - speculation is well underway to explain the mechanism for renal protection. And the emerging story appears to be quite fascinating indeed.
Data from the EMPA-REG study were unveiled in Stockholm 6 weeks ago. In more than 7,000 adults with type 2 diabetes (T2D) at high risk for CV events, EMPA-REG OUTCOME met its primary endpoint and demonstrated superiority of JARDIANCE, when added to standard of care, in CV risk reduction. The primary endpoint was defined as time to first occurrence of either CV death, or non-fatal myocardial infarction or non-fatal stroke.
Canada becomes the first country outside Japan to approve JinarcTM (Tolvaptan) for the treatment of ADPKD. This medication, dosed twice daily, is the first of its kind to show a slowing in renal function decline as well as a slowing in kidney enlargement among patients with ADPKD.
Previously, UKidney News reported a possible link between calcium channel blockers and the development of breast cancer. Data from the Intermountain Medical Center Heart Institute study were presented at the 2014 American Heart Association Scientific Sessions in Chicago, dispelling some of this concern:
"We found no robust data that calcium channel blocker medications increase a person's risk of breast cancer," said Jeffery L. Anderson, MD, a cardiologist and researcher at the Intermountain Medical Center Heart Institute. "Given the important role calcium channel blocker medications play in treating heart conditions, we think it's premature to discontinue their use. At this point we recommend that patients continue taking these medications to treat their hypertension."
While it is very difficult to ever prove a negative association, these data do provide some reassurance to a large number of patients using this important antihypertensive.
Imagining the Dream RCT in nephrology is an important exercise, but not for the reasons you might think. For many, there might be the temptation to devise trials that will pave the way for future enhancements to patient care or to some other exciting, forward thinking outcome. For me however, the Dream RCT in nephrology is about shattering or affirming nephrology dogma - and in nephrology we seem to have more dogma influencing core tenets of our specialty than in other medical disciplines. There is a popular saying among those in the clinical epidemiology world - that you don’t need to conduct an RCT to prove that parachutes are required when jumping out of a plane. Unfortunately in nephrology, thought leaders have bestowed parachute status on too many interventions. I can think of no better example for this analogy than treating hyperphosphatemia in CKD/ESRD. And it is this topic that would underlie my Dream RCT.
Top-line results of the Symplicity 3 trial were revealed this week, showing that despite being safe, renal denervation was no better than a sham procedure at controlling blood pressure at 6 months. As reported on Medscape:
A report in JAMA - Internal Medicine raises important safety concerns about calcium channel blockers, one of the most widely prescribed classes of antihypertensives used world-wide.
In the population-based case-control study by Li et al, participants in the 3-county Seattle–Puget Sound metropolitan area were women aged 55 to 74 years, 880 of them with invasive ductal breast cancer, 1027 with invasive lobular breast cancer, and 856 with no cancer serving as controls. The exposures studied were recency and use of antihypertensive medications while the main outcome measures were risks of invasive ductal and invasive lobular breast cancers.
As reported on UKidney, earlier in July 2013, Jamal et al published a systematic review comparing calcium-based phosphate binders with non-calcium-based phosphate binders in terms of their impact on cardiovascular outcomes. This pivotal work shows a small but statistically significant advantage of non-calcium-based binders over calcium vis-à-vis mortality outcomes in patients with chronic kidney disease and hyperphosphatemia.
Calcium dose has been implicated in the development of vascular calcification and in the excess cardiovascular morbidity common in patients with CKD, especially those on dialysis. The hope for non-calcium-based phosphate binders has always been that by limiting calcium intake, patients taking non-calcium-based binders would benefit from phosphate reduction without the exposure to potentially harmful dosages of calcium. While individual clinical trials have failed to show any clear advantage of non-calcium-based phosphate binders in terms of reducing cardiovascular morbidity and mortality, this latest systematic review now shows a statistically significant advantage of non-calcium-based phosphate binders over calcium in terms of limiting mortality in patients with CKD.
So where do we go from here? There will likely be discussion as to whether the finding in this systematic review is valid. Furthermore, even if the effect is indeed real, the cost of non-calcium-based binders over calcium-based binders is substantial. Nevertheless, it is likely time to consider whether calcium-based phosphate binders should be made obsolete. There are now substantial data supporting at least a modest effect of calcium dose on mortality and the rationale for using phosphate binders that are not calcium-based. An important question remains as to whether hyperphosphatemia should be treated at all – that is, with binders of any sort. It is entirely possible that non-calcium-based phosphate binders are superior to calcium simply because they limit calcium intake and that the drugs themselves do not offer any other outcome advantage - even if they lower phopshate.
And so, while this systematic review comes closer to answering a long-standing question in nephrology related to optimal phosphate binder class, it underscores an important lingering question as to whether hyperphosphatemia requires treatment at all. To answer this critical question, we require a long overdue placebo-controlled trial of hyperphosphatemia treatment. Objections to a placebo-controlled trial in this area have often centered around the ethics of withholding treatment for hyperphohsphatemia in the form of phosphate binders. However, there appears to be equipoise in this area; there is real uncertainty as to the saftey of calcium-based phosphate binders and whether hyperphosphatemia truly mediates cardiovascular illness in patients with CKD, or if it is only a disease association and nothing more.